CN102139110A - Use of angiotensin II receptor antagonists, especially telmisartan, in order to increase insulin sensitivity - Google Patents

Use of angiotensin II receptor antagonists, especially telmisartan, in order to increase insulin sensitivity Download PDF

Info

Publication number
CN102139110A
CN102139110A CN2011100821828A CN201110082182A CN102139110A CN 102139110 A CN102139110 A CN 102139110A CN 2011100821828 A CN2011100821828 A CN 2011100821828A CN 201110082182 A CN201110082182 A CN 201110082182A CN 102139110 A CN102139110 A CN 102139110A
Authority
CN
China
Prior art keywords
purposes
patient
angiotensin
glucose
telmisartan
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN2011100821828A
Other languages
Chinese (zh)
Inventor
斯蒂芬.考希克
迈克尔.马克
乌尔里克.金斯彻尔
迈克尔.舒普
托马斯.昂格尔
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=34119379&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN102139110(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Publication of CN102139110A publication Critical patent/CN102139110A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Landscapes

  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Emergency Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

The present invention relates to the use of angiotensin II receptor antagonists for the treatment of people who have been diagnosed with type 2 diabetes mellitus, or are thought to have prediabetes, in order to prevent diabetes or for the treatment of metabolic syndrome and the resistance of insulin in patients having normal blood pressure.

Description

Angiotensin ii receptor antagonist is used to improve the purposes of insulin sensitivity
The application is that (denomination of invention: angiotensin ii receptor antagonist, particularly telmisartan are used to improve the purposes of insulin sensitivity to Chinese patent application; Application number: 200480022096.6; The dividing an application applying date: on 07 24th, 2004).
Technical field
The invention belongs to the angiotensin ii receptor antagonist field, and relate to it and be used for the treatment of and be diagnosed as diabetes or suspection has prediabetes
Figure BDA0000053409160000011
The people, be used for prevent diabetes or be used for the treatment of the metabolic syndrome of blood pressure normal patient and the purposes of insulin resistance.
Background technology
The true property of 2 types diabetes are symptom of two kinds of pathophysiology phenomenons, promptly by the secretion of insulin minimizing of pancreatic beta cell and the insulin resistance of Target organ liver, skeletal musculature and fatty tissue.Usually the plyability pathological changes that has these two kinds of compositions.This disease is diagnosed as empty stomach-hyperglycemia, and blood sugar concentration surpasses the ultimate value of 125mg glucose/dl blood plasma after promptly fasting 10-12 hour.Chemical compound by thiazolidinedione (lattice row ketone Glitazone) material type can effectively be treated tangible type 2 diabetes mellitus.These chemical compounds improve the utilization of circulation insulin, therefore make blood glucose value decline (insulin sensitivity agent).Simultaneously, by feedback mechanism, higher amount of insulin is reduced, thereby alleviates the pancreas burden.Such as troglitazone (Troglitazone), Loews lattice row ketone (Rosiglitazone) or the insulin sensitivity agent such as (Pioglitazone) of Pi Aogelie ketone by being attached on the particular core receptor that is called PPAR-γ (peroxisome proliferant agent activated receptors, Peroxisomal Proliferator Activated Receptor) and play a role.These are a series of to glucose metabolism and the significant gene of lipid metabolism as transcribing the controlling agent influence.By these functions, help to treat type 2 diabetes mellitus such as the PPAR-γ part of prostaglandin or synthetic thiazolidinedione (lattice row ketone).The dominant mechanism that glucose is descended by PPAR-γ part is the differentiation of induced lipolysis cell.The differentiation of reinforcement adipose cell and the fatty tissue remodeling that cause by PPAR-γ part make the free fatty acid change or the reallocation of skeleton-musculature be fatty tissue, thereby have improved the glucose metabolism in the muscle.
Because when diagnosis, for example per two type 2 diabetes mellitus patients show all a coronary heart disease symptom, therefore think, the diabetes reason of the unusual middle increase of plyability substance metabolism can be inferred and shows as a series of risk factors, as the disorder of glucose patience, fasting glucose rising, insulin resistance, hypertension, lipid obstacle (Dyslipidamle) or body obesity.For patient with hypertriglyceridemia and low HDL-cholesterol, the universality of insulin resistance
Figure BDA0000053409160000021
Be tangible especially.Be referred to as forerunner's type 2 diabetes mellitus, metabolic syndrome, syndrome X or insulin resistance syndrome.In the phase I, the insulin replies of Target organ reduces the insulin secretion that causes pancreas and raises, so that blood sugar level remained in normal range.After the insulin output of too high or rising for many years, cause the insulin discharge of pancreatic beta cell further not raise.Thereby the glucose patience stage of beginning pathological changes.Organism no longer can absorb glucose peak fast enough.Final fasting blood sugar continues higher, then shows as diabetes.
WO95/06410 discloses the purposes that angiotensin ii receptor antagonist is used for the treatment of the chronic inflammatory disease that comprises systemic autoimmune disease.Diabetes are one of numerous examples of systemic autoimmune disease.This autoimmune disease belongs to the true property of 1 type diabetes, appears at mostly below 30 years old in the youngster, wherein, has corresponding heredodiathesis, under different factor affecting, along with taking place subsequently, beta cell produces insulitis unusually, and pancreas less produces maybe and can not produce insulin as a result.The true property of 2 types diabetes are not regarded as autoimmune disease.
Angiotensin ii receptor antagonist is used to treat hypertension and infringement continuously
Figure BDA0000053409160000022
The cardiovascular terminal organ relevant with hypertension.In technical literature, usually it is classified as metabolism neutrality (metabolisch neutral).People such as Henriksen report can improve insulin sensitivity (Hypertension 38:884-90,2001) by active substance irbesartan (Irbesartan) in animal model.
Summary of the invention
The purpose of this invention is to provide a kind of medicine, this medicine both can be used for the treatment of tangible type 2 diabetes mellitus, also can be used for the treatment of the unusual initial symptom of prediabetic plyability substance metabolism, therefore can be used to prevent the true property of 2 types diabetes.Within the scope of the present invention, find surprisingly now, a few angiotensin ii receptor antagonist and salt thereof can also reinforcing gene expression in cell system except the known effect of bringing high blood pressure down, and known this gene transcription is controlled by PPAR γ receptor.The new treatment of treatment and prevention type 2 diabetes mellitus, metabolic syndrome and insulin resistance is also disclosed.In order to guarantee comparable condition, within the scope of the present invention, observe and quantize this effect by the cell line (referring to embodiment 2) of stable conversion (transormierten).Relate to the CHO-cell at this, it is the conversion results with two kinds of gene configurations.First kind of configuration encoded by the luciferase gene (deWet JR, Mol Cell Biol (1987) 7:725) of Photinus pyralis, and it is to have five repetition yeast Gal4-binding sites (referring to gene bank-sequence AF058756) synthetic promoter control under carry out.Second kind of configuration encoded by people PPAR γ 2 transcription factor (referring to gene bank-sequence U79012) ligand binding domain and yeast GAL4DNA in conjunction with territory (amino acid/11-147; Sadowski I, Nucleic Acids Res (1989) 17:7539) fusion rotein of being formed.
Known to the genetic transcription of PPAR γ control being induced as the thiazolidinedione (for example, Loews lattice row ketone) of antidiabetic drug, and be attached on the PPAR γ receptor and activation is worked by it.In the test macro scope used herein, this effect can quantize the effect as the inductive uciferase activity of cell transformed system.Against one's expectation, angiotensin ii receptor antagonist is not to be attached on the receptor PPAR γ by active substance to inducing of uciferase activity and realizes.This is induced for the active substance telmisartan is outstanding especially.Can not confirm that in different test macros for example telmisartan is attached on the PPAR γ receptor.Therefore think, when the synthetic PPAR γ that does not have high affinity-part, cause that by angiotensin ii receptor antagonist such as telmisartan improving cofactor albumen can also carry out also to the affinity of PPAR γ that cofactor is proteic to be replenished.This causes the activation to the genetic transcription that is subjected to the control of PPAR γ receptor by the mediation of this cofactor.Because inducing of this gene is relevant with the antidiabetic effect of thiazolidinedione, therefore think thus, induce same gene can bring into play comparable antidiabetic effect by hypertensin 11 receptor antagonist such as telmisartan.Therefore this active substance not only is suitable for treating hypertension, but also is suitable for treatment and prevents the true property of 2 types diabetes.
This new therapeutical effect of finding angiotensin ii receptor antagonist and salt thereof means that it can be used to prepare a kind of medicine; this medicine is used for the treatment of and is diagnosed as 2 types true property diabetes or suspection has prediabetic people, is used for prevent diabetes or is used for the treatment of the metabolic syndrome and the insulin resistance of blood pressure normal patient.It is particularly suitable for treatment and prevention type 2 diabetes mellitus and forerunner's type 2 diabetes mellitus.Comprise treatment and prevention metabolic syndrome, syndrome X or insulin resistance syndrome.For people to be treated in the scope of the invention, though treatment is mainly introduced in the front or prevention is human, employed active substance and active compound composition can also correspondingly be used for the mammal of veterinary.
The true property of 2 types diabetes show as at fasting blood sugar and surpass 125mg glucose/dl blood plasma, and wherein, dextrose equivalent is the standard method of medical science conventional analysis in the mensuration blood.If carry out the test of glucose patience, then take in the 75g glucose after 2 hours on an empty stomach, diabetes patient's blood glucose value surpasses 200mg glucose/dl blood plasma.In the test of glucose patience, patient to be tested is oral 75g glucose after fasting 10-12 hour, and checks immediately and take in before the glucose and 1 or 2 hour the blood glucose value in absorption back.For healthy people, this blood glucose value is 60～110mg/dl blood plasma before absorption, takes in back 1 hour and is lower than 200mg/dl, is lower than 140mg/dl after 2 hours.If this value is 140～200mg after 2 hours, it is unusual then to can be considered glucose patience.
Having prediabetic special distinguishing mark is to be proved to be insulin resistance.So, if to keep glucose homology balance then the amount of required insulin be that other people 2-3 doubly measures, otherwise direct pathological phenomenon will appear.Blood glucose is normal-and hyperinsulinemia anchor clamps (Clamp)-test is the method for effective definite insulin resistance.In the insulin-glucose-notes transferring technology scope of combination, measure the ratio of insulin and glucose.Tried 25% of background population if glucose uptake is lower than, then explanation has insulin resistance (WHO definition).Than these anchor clamps-testization expense lower be so-called least model, in this model, in intravenous glucose patience test process,, thereby calculate insulin resistance with insulin concentration and concentration of glucose in the time interval measurement blood of determining.Another kind of assay method is a mathematics HOMA model.Calculate insulin resistance by fasting plasma-glucose and fasting insulin concentration.In these method scopes, can not distinguish the insulin resistance of liver and periphery.These methods seldom are applicable to the insulin resistance of estimating in the daily reality.Daily clinical in, introduce other parameters usually and assess insulin resistance.For this reason, preferably introduce for example patient's triglyceride concentration, because the triglyceride levels that raises is obviously relevant with the existence of insulin resistance.
In the reality,,, then think this artificial insulin resistance if having at least 2 kinds of following features for for simplicity:
1) overweight or fat
2) hypertension
3) dyslipidemia (total lipid content changes in the blood)
4) has a close relative who is diagnosed as the unusual or type 2 diabetes mellitus of glucose patience at least.
Overweight being meant in the literary composition, body-mass index (BMI) is 25 and 30kg/m 2Between, the merchant of BMI body weight of representing with kg and the height of representing with rice square wherein.When fat, BMI is greater than 30kg/m 2
Can find out directly that from the definition of above insulin resistance if determine that the patient particularly has the hypertension character, then for to its treatment, hypotensive agent is to be fit to and effectively.Present result of the present invention is, several angiotensin-ii receptor inhibitor are arranged, and telmisartan especially wherein is because the preferably hypotensive agent of its PPAR-γ activation character, if determine that the patient does not have hypertension but blood pressure just often, it also is suitable for treating insulin resistance.Therefore can use telmisartan treatment type 2 diabetes mellitus people, be used for the treatment of simultaneously or supportive treatment dyslipidemia.The telmisartan of routine dose plays the effect of the blood plasma value that obviously reduces LDL-cholesterol, T-CHOL and/or triglyceride.
Because insulin resistance is considered to the situation that causes that blood pressure raises gradually, so can treat with telmisartan, although pressure value is normal, then is regarded as prophylaxis of hypertension.
Prediabetic similar sign is the condition that meets metabolic syndrome, and its principal character is an insulin resistance.According to ATP IHINCEP guide (Executive Summary of the Third Report of theNational Cholesterol Education Program (NCEP) im Journal of the AmericanMedical Association 285:2486-2497,2001), if the patient has at least 3 kinds of following features, then explanation has metabolic syndrome:
1) abdominal obesity is defined as, male's waistline＞40 inch or 102cm, women＞35 cun or 94cm
2) triglyceride value＞150mg/dl
3) male HDL-cholesterol value＜40mg/dl
4) hypertension＞130/＞85mm Hg
5) fasting glucose＞110mg/dl
Can find out directly that from this metabolic syndrome definition if determine that the patient particularly has hypertension, then for it is treated, hypotensive agent is fit to.Present result of the present invention is, several angiotensin-ii receptor inhibitor are arranged, but telmisartan especially, because the preferably hypotensive agent of its PPAR-γ activation character, if when determining that the patient does not have hypertension, it also is suitable for treating insulin resistance.Because metabolic syndrome also is considered to the situation that causes that blood pressure raises gradually, so can treat with telmisartan, although pressure value is normal, then can be regarded as prophylaxis of hypertension equally.
If fasting blood sugar surpasses maximum normal value 110mg glucose/dl blood plasma, but is no more than the ultimate value 125mg glucose/dl blood plasma relevant with diabetes, then also can suspect has prediabetes.Another sign of prediabetes is that glucose patience is unusual,, in glucose patience test specification, takes on an empty stomach behind the 75g glucose 2 hours that is, and blood glucose value is 140-200mg glucose/dl blood plasma.
The blood values of triglyceride also can be thought greater than 150mg/dl and has prediabetes.Low HDL-cholesterol blood value has been strengthened this suspection.The women is lower than the value of 40mg/dl blood plasma, and the value that the male is lower than 50mg/dl blood plasma is considered to too low.Triglyceride and HDL-cholesterol belong to the standard method in the medical analysis equally in the mensuration blood, and for example be described in: Thomas L (Hrsg.): Labor undDiagnose "; TH-Books Verlagsgesellschaft mbH, Frankfurt/Main is in 2000.In addition, if fasting blood sugar surpasses 110mg glucose/dl blood plasma, then more definite to prediabetic suspection.If the blood values that records then can be with WHR as additional auxiliary judgment in the ultimate value scope.If this ratio women surpass 0.8 or the male surpass 1, then show and need treat.
If also must treat hypertension, then particularly point out, angiotensin ii receptor antagonist can be used for treating diabetes or possible prediabetes.If the systolic blood pressure value surpasses 140mm Hg and the diastolic blood pressure value surpasses 90mm Hg, is exactly this situation.If a patient has suffered from obvious diabetes, recommendation now will drop to the systolic blood pressure value below the 130mm Hg, and the diastolic blood pressure value is dropped to below the 80mm Hg.In order to reach above-mentioned value, look concrete condition separately, can be used in combination angiotensin ii receptor antagonist and diuretic or calcium antagonist." diuretic " comprises thiazine or thiazine analog to term, example hydrochloric acid thiazine (HCTZ), brinaldix, uncommon handkerchief amide or chlortalidone, aldosterone-antagonist, as spironolactone or eplerenone (Eplerenone), also have other to be fit to the hypertensive diuretic of treatment, as furosemide and pirbuterol (Piretanide), and they and amiloride (Amiloride) and Ademine (triamterene) are used in combination.
The present invention shows that for the people that will treat because of hypertension, if need the prevent diabetes development or treat tangible diabetes, then angiotensin ii receptor antagonist is always desirable as telmisartan.
Have only 10% can determine provable reason, for example nephropathy in all hypertension (secondary hypertension) situation.By treating and getting rid of this reason, can eliminate secondary hypertension usually.But nearly 90% of all situations is an essential hypertension, does not also know its accurate reason, thereby can not directly cure.Can reduce hypertensive negative effect by changing living habit and correct treatment.It seems that synergism different or the common various risk factors that occur cause hypertension.Particularly, observe the situation that hypertension and lipid metabolism and abnormal carbohydrate metabolism occur simultaneously.These unusual initial often be unconspicuous, but can learn by the higher blood values of triglyceride and glucose and the lower blood values of HDL-cholesterol.In developmental stage, also help to find out from the obesity that increases gradually.These can be made an explanation by the insulin resistance increase unusually.The insulin effectiveness is more little, and lipid metabolism and carbohydrate metabolism are just chaotic more.All these unusual combinations have finally increased the probability of suffering from diabetes and dying from heart disease or angiopathy too early.
Infer thus, the situation that about 1/3rd excessive generation hypertension of its nutrition supply of adult and fat and sugar Developmental and Metabolic Disorder occur together in the world wide, and this quantity is also increasing.Therefore need a kind of medicine, this medicine helps to delay or stop the unusual development of described substance metabolism at commitment as far as possible in the case, avoids the hypertensive influence that is harmful to health simultaneously.
The present invention also discloses a kind of medicine, and it not only can be used for the treatment of hypertension, also can be used for the treatment of tangible type 2 diabetes mellitus or the unusual initial stage symptom of prediabetic plyability substance metabolism.Therefore, the present invention also comprises the diabetes mellitus prevention because of the subject patient of hypertension.Therefore,, then use suitable angiotensin ii receptor antagonist such as telmisartan at once, thereby can delay or avoid occurring obvious type 2 diabetes mellitus with controlling blood pressure if there is prediabetic above-mentioned symptom.
Suitable within the scope of the present invention angiotensin ii receptor antagonist is such chemical compound, can get rid of it in testing in vitro (referring to embodiment 1) is attached on the PPAR γ ligand binding domain, and on its cell, promptly, after the PPAR γ that adds stable conversion-report (reporter) cell was tied in the culture medium, it activated the expression (referring to embodiment 3) of the luciferase gene of same stable transfection.
Suitable angiotensin ii receptor antagonist also shows
● on the external ligand binding domain that is not attached to people PPAR γ receptor, but
If ● it is joined in the culture medium of the PPAR γ of stable conversion-report daughter cell system the plain enzymatic activity of induced fluorescence then, this cell line
A) express a kind of fusion rotein of forming in conjunction with the territory by the ligand binding domain and the yeast GAL4DNA of people PPAR γ transcription factor, and
B) contain a kind of luciferase gene under five multiple yeast Gal4-binding site control.
The preparation of this PPAR γ-report daughter cell system has been described in embodiment 2.
If in α screening people such as (, Proc Natl Acad Sci USA (1994) 91:5426-5430) Ullmann EF, can not detect, then not be attached on people PPAR γ 2 receptor ligand binding domains external.Replace the α screening, can also carry out SPA-test people such as (, J Steroid Biochem MolBiol (2002) 81:217-225) Mukherjee R or NMR-test people such as (, J Mol Biol (2000) 298:187-194) Johnson BA.Usually these method neither ones can detect and be attached on the receptor.
List angiotensin ii receptor antagonist in detail at the 7-18 of WO 95/26188 page or leaf.Angiotensin ii receptor antagonist also is described among EP-A-253310, EP-A-323841, EP-A-324377, EP-A-420237, EP-A-443983, EP-A-459136, EP-A-475206, EP-A-502314, EP-A-504888, EP-A-514198, WO 91/14679, WO 93/20816, US 4355040 and the US 4880804 in addition.The embodiment of often mentioning is husky smooth class, pounces on Sha Tan (Eprosartan), irbesartan (ibesartan), losartan (Losartan), Ao Mishatan (Olmesartan), Te Suoshatan (Tasosartan), telmisartan (telmisartan) or valsartan (Valsartan) as Candesartan (Candesartan), Chinese mugwort.As particularly preferably being irbesartan, losartan and telmisartan within the scope of the present invention.Clearly can reach best effects with telmisartan and salt thereof.It is 20-200mg that the form of administration that makes contains equivalent, preferred 20,40,80,120,160 or the active substance free acid of 200mg.If the combination of active substance and HCTZ or chlortalidone, then form of administration contains 10-50mg, preferred 50,25 or the diuretic of 12.5mg.
The favorable activity of disclosed each Angiotensin II antagonist in the scope of the invention is outstanding especially with regard to the active substance telmisartan.Be used in combination angiotensin-ii receptor inhibitor and one or more other treatment active substances and it seems it is suitable or necessary, telmisartan is preferred angiotensin-ii receptor inhibitor, because its with independent active substance combination have blood pressure lowering and a metabolic activity, for example anti-diabetic activity also helps prevent diabetes.Owing to this reason, by telmisartan and the active compound composition of being prepared such as the HMG-Co A reductase inhibitor of simvastatin (Simvastatin) or atorvastatin (Atorvastatin), in treatment cardiovascular diseases, heart and lung diseases, pneumonopathy or nephropathy, and in treatment dyslipidemia, osteoporosis or Alzheimer, constituted a kind of great development.The active compound composition of telmisartan and Loews lattice row ketone or Pi Aogelie ketone or repaglinide (Repaglinide) or metformin (Metformin) or DPP4 inhibitor also is applicable in the treating diabetes.And with renin-angiotensin system (RAS) inhibitor and calcium antagonist such as amlodipine (Amlodipine) or nifedipine (Nifedipine) or aldosterone antagonists such as spironolactone or eplerenone (eplerenone) combined therapy hypertension the time, must look telmisartan is preferred RAS inhibitor.Be used for the treatment of with the compositions of aldosterone antagonists such as eplerenone or prevent to have a weak heart or myocardial infarction also is a kind of great development.
Except hypertension, lipid metabolism unusual (dyslipidemia) and true property diabetes also mean higher risk of stroke, so telmisartan is also in conjunction with platelet-agglutination inhibitor such as clopidogrel (Clopidogrel) or dipyridamole (persantin, Dipyridamol), make up aspirin (ASA) in case of necessity in addition, be a kind of preferred combination collocation agent, be used in particular for prevention of stroke.For this purpose, can be with 50～750mg, the dosage of preferred 100～500mg, particularly 200～450mg uses dipyridamole.Can be with 10～200mg, the dosage of preferred 25～100mg, particularly 30～75mg uses ASA.
Therefore, another theme of the present invention is pharmaceutical composition and preparation thereof, and said composition comprises telmisartan or its a kind of salt with following combination
● amlodipine or nifedipine,
● eplerenone or spironolactone,
● simvastatin or atorvastatin,
● Loews lattice row ketone or Pi Aogelie ketone or repaglinide (Repaglinide) or metformin,
● dipyridamole or clopidogrel, make up aspirin in case of necessity,
● sulfonylureas,
● aldosterone antagonists,
● the HMG-CoA reductase inhibitor,
● the DPP4 inhibitor or
● platelet-agglutination inhibitor.
Usually be added with one or more formulation adjuvants in the active compound composition of this preparation, for example, mannitol, Sorbitol, xylitol, sucrose, calcium carbonate, calcium phosphate, lactose, cross-linking sodium carboxymethyl cellulose salt (cellulose carboxyl methyl ether sodium salt, crosslinked), crospolyvinylpyrrolidone, sodium starch glycollate, hydroxy propyl cellulose (low replacement), corn starch, polyvinylpyrrolidone, the copolymer of vinylpyrrolidone and other ethenyl derivatives (Copovidone), hydroxy propyl cellulose, HYDROXY PROPYL METHYLCELLULOSE, microcrystalline Cellulose or starch, magnesium stearate, stearyl fumarate, Talcum, HYDROXY PROPYL METHYLCELLULOSE, carboxy methyl cellulose, cellulose acetate phthalate, polyvinyl acetate, water, water/ethanol, water/glycerol, water/Sorbitol, water/Polyethylene Glycol, propylene glycol, cetostearyl alcohol, carboxy methyl cellulose, or fatty material, for example stearic or its suitable mixture, with the lid Lun Shi preparation of routine, as tablet, the sugar-coat agent, capsule, powder, suspension or suppository are processed.
Tablet for example by mixing one or more active substances and one or more auxiliary agents, and is suppressed subsequently, and is made.This tablet can also be made up of multilamellar.The example of auxiliary agent is
● inert diluent, as mannitol, Sorbitol, xylitol, sucrose, calcium carbonate, calcium phosphate and lactose;
● disintegrating agent, as cross-linking sodium carboxymethyl cellulose salt (cellulose carboxyl methyl ether sodium salt, crosslinked), crospolyvinylpyrrolidone, sodium starch glycollate, hydroxy propyl cellulose (low replacement) and corn starch;
● binding agent, as copolymer (Copovidone), hydroxy propyl cellulose, HYDROXY PROPYL METHYLCELLULOSE, microcrystalline Cellulose or the starch of polyvinylpyrrolidone, vinylpyrrolidone and other ethenyl derivatives;
● lubricant, as magnesium stearate, stearyl fumarate and Talcum;
● be used to realize depositing the reagent of purpose, as HYDROXY PROPYL METHYLCELLULOSE, carboxy methyl cellulose, cellulose acetate phthalate and polyvinyl acetate; With
● the coloring agent that medicine allows, as colored iron oxides.
The blocking-up sterone can reduce and has mortality in said patients and the sickness rate that obviously has a weak heart.Have a weak heart and the incompetent patient who suffers from myocardial infarction and adopt ACE inhibitor, angiotensin receptor antagonist, diuretic or beta blocker treatment of left ventricle because of symptomatic, can show, can increase its chance of surviving with the other treatment of selectivity aldosterone blocker eplerenone, and cause reducing subsequently hospital (NEJM 348:1309-1321,2003).In the patient's group that is studied, also comprise (miterfasst) diabetics, though there is left ventricle insufficiency in it, but there be not symptomatic having a weak heart, for this group patient, the danger of cardiovascular situation is same big with the danger with left ventricle insufficiency and the symptomatic patient of having a weak heart.Given this, so the antidiabetic effect of angiotensin-ii receptor blockers telmisartan disclosed herein means, itself and eplerenone are combined in when treating myocardial infarction thereafter have been suffered from diabetes and diabetic albuminuria disease has been arranged sometimes those especially, perhaps suspects to be that prediabetic patient is necessary.Therefore theme of the present invention also is pharmaceutical forms of administration, wherein makes up two kinds of active substance telmisartans and eplerenone, and for example equivalent is 40-320mg, preferred 80 or telmisartan and the equivalent of 160mg be 20-200mg, preferred 25 or the eplerenone of 50mg.A kind of preferred form of administration is two-layer tablet.In order to treat this patient who has dyslipidemia symptom (for example hypertriglyceridemia or hypercholesterolemia) simultaneously, with routine dose 2.5-40mg, preferred 5,10,15,20,25,30,35 or lipid lowering agent such as the simvastatin of 40mg or the additional set compound of atorvastatin usually be significant.The corresponding preparations of telmisartan, eplerenone and atorvastatin or simvastatin for example can be made tri-layer tablets.Particularly with D 90Particle diameter is that the micronization form of 25-400 micron is used active substance eplerenone (referring to WO 00/33847).
Metformin is a kind of potent antidiabetic medicine, and it mainly acts on is that too high glucose yield realizes in the diabetes patient liver by reducing.In true property treatment of diabetes was observed, the non-enzyme of HbA1c-value, a kind of hemoglobin B-chain urged sweet oiled product to have outstanding meaning.Because its formation depends primarily on blood sugar level and red blood cell life span, so HbA1c is reflected in over the average blood sugar level in 4-6 week in the meaning of " blood glucose memory ".Diabetics, its HbA1c-value obtains lasting well-tuned (promptly in sample＜6.5% total hemoglobin) by the treating diabetes of strengthening, and obtains obvious better protection before diabetic microangiopathy occurs.For the diabetes patient, metformin can reach the average improvement of the HbA1c value of 1.0-1.5% magnitude separately.This HbA1c value reduction be not that all diabetes patients are enough to reach desirable＜6.5% target zone, the HbA1c of preferred＜6%.Therefore, in order to strengthen the effect of metformin, need take to treat in addition measure.
Find surprisingly that within the scope of the present invention telmisartan plays the effect of PPAR-γ activator.Therefore telmisartan have improve fat-, muscle-and the potentiality of the insulin sensitivity of hepatic tissue, blood glucose is descended.This makes telmisartan become antidiabetic drug such as metformin or the specially suitable combination collocation agent of repaglinide (promoting from the pancreatic beta cell uelralante), because it acts on based on other action principle, thereby help strengthening the model of action of this active substance.The formulation example of the combination of repaglinide and telmisartan is 0.25～5mg as containing equivalent, preferred 0.25～2mg, preferred especially 0.5 or 1 or repaglinide and the equivalent of 2mg be 40-320mg, preferred 80 or the 160mg telmisartan.
The compositions of telmisartan and metformin is particularly suitable for fat type 2 diabetes mellitus people, because, on the one hand, metformin is different from another kind of oral antidiabetic drug, do not cause weight increase, on the other hand, it is its most important characteristic that telmisartan reduces insulin resistance, and is the cause of the higher blood sugar level of type 2 diabetes mellitus people.For most fat type 2 diabetes mellitus people and prediabetes people, if determine hypertension, it also belongs to the standard of metabolic syndrome.For this patient's group, telmisartan is a kind of preferred antihypertensive, its another character is advantageously to work with a kind of potent antidiabetic medicine such as metformin as the insulin sensitivity agent, so that also similarly treat the different aspect of following disease simultaneously: type 2 diabetes mellitus, forerunner's type 2 diabetes mellitus or metabolic syndrome or insulin resistance.Can additionally improve the HbA1c value by replenishing the adding telmisartan, reach grade 0.25-2%, preferred 0.25-1%, preferred especially 0.25-0.5%.In addition, improve the HbA1c value and mean that less than total hemoglobin 0.25% to treatment type 2 diabetes mellitus people be significant help; But can not measure at present.Studies show that as UKPDS (UnitedKingdom Prospective Diabetes Study), it also is effective reducing too high blood pressure the same with the blood sugar lowering therapy, thereby reduce type 2 diabetes mellitus people late complication, as nephropathy, neuropathy, retinopathy, and all trunks
Figure BDA0000053409160000111
Complication.Therefore, the telmisartan that provides and the combination of metformin are a kind of for reducing or even preventing that the serious consequence of diabetes from mainly contributing.
The combination preparation of metformin and telmisartan contains for example normal 450-900mg, and preferred 500 or metformin and the normal 40-320mg of 850mg, preferred 80 or the telmisartan of 160mg.Metformin has good solubility, can be without a doubt prepares with auxiliary agent such as binding agent and lubricant.A kind of preferred form of administration is two-layer tablet.Form the combination of preferred active matter quality and amount of auxiliary with following amount:
Table 1: tablet with 80mg telmisartan
Figure BDA0000053409160000121
Table 2: tablet with 160mg telmisartan
Figure BDA0000053409160000122
The preparation of repaglinide and telmisartan combination contains for example normal 0.25～5mg, preferred 0.25～2mg, preferred especially 0.5 or 1 or repaglinide and the normal 40-320mg of 2mg, preferred 80 or the telmisartan of 160mg.
The specific embodiment
Embodiment:
Embodiment 1: telmisartan, losartan and irbesartan are not attached on the PPAR γ ligand binding domain external
Preparation contains the protein of people PPAR γ-ligand binding domain (LBD) in escherichia coli, as the GST-fusion rotein, and carries out purification with the affinity chromatography.
Through in expression vector pGEX-4T-1 (Amersham), importing in addition restricted cleavage site BamH I and Xho I, sub-clone one dna fragmentation, the aminoacid 205-505 of its coding people PPAR γ 2-transcription factor is (referring to gene bank-enter U79012), and the control fragments sequence.Under 25 ℃, induce 4 hours with 0.2mM IPTG after, the escherichia coli-strain BL21 (DE3) recommending to be used for the pGEX carrier carries out Expression of Fusion Protein.And then make bacterial precipitation after inducing, and in PBS, pH7.4 freezing in batches (weggefroren).According to the explanation of French Press, by the dissolved GST-PPAR γ of GSTrap-post (Pharmacia) purification-LBD-fusion rotein.Add the reductive glutathion of 20mM and carry out eluting.
By HiTrap desalting column (Pharmacia) to GST-PPAR γ-LBD-protein fractional distillation with desalination, measure protein concentration with ortho-test.
Preparation contains the protein of people RXR α-ligand binding domain (LBD) in escherichia coli, as the Histag-fusion rotein, and uses the affinity chromatography purification.Through in expression vector pET28c (Novagen), importing restricted cleavage site BamH I and Not I in addition, sub-clone one dna fragmentation, the aminoacid 220-461 of its coding people RXR α-transcription factor (referring to gene bank-enter NM 002957, nt729-1457), and the control fragments sequence.Under 25 ℃, induce 4 hours with 0.2mM IPTG after, the escherichia coli-strain BL21 (DE3) recommending to be used for the pET carrier carries out Expression of Fusion Protein.And then make bacterial precipitation after the expression, and freezing in batches in PBS, pH7.4.According to the explanation of French Press, by the dissolved His-RXR α of HiTrap chelate column (Pharmacia) purification-LBD-fusion rotein.(stufe) carries out eluting by 500mM imidazoles-step.By HiTrap desalting column (Pharmacia) His-RXR α-LBD-protein fractional distillation is carried out desalination, measured protein concentration with ortho-test.A) α screening
α screening-test is described in people such as Ullmann EF at first, among Proc Natl Acad Sci USA (1994) 91:5426-5430.In the present embodiment according to People such as Glickman JF, the description of J Biomol Screen (2002) 7:3-10 is measured.Test-buffer is made up of 25mM Hepes pH7.4,100mM NaCl, 1mM DTT, 0.1%Tween-20,0.1%BSA.The biotinylation LXXLL-peptide of 3nM GST-PPAR γ-LBD-fusion rotein, 15nM cofactor CBP (is equivalent to people such as Mukherjee R, 218 pages of disclosed peptides of JSteroid Biochem Moi Biol (2002) 81:217-225, cysteine with a kind of other N-terminal), and in each case, anti--GST-acceptor bead or the strepto-of 10 μ g/ml are given birth to plain (Streptavidin-) donor bead (Applied Biosystems), in the 12.5 μ l cumulative volumes in the presence of the experiment material (in DMSO) of variable concentrations, incubated at room temperature 4 hours.Final DMSO concentration in the test is 1% (v/v).1% DMSO solution contrasts (NSB) as a setting.On Packard fusion-measuring instrument, measure.
Figure BDA0000053409160000141
Different with Loews lattice row ketone, document is disclosed, bonded PPAR γ-agonist passes through cumulative telmisartan, losartan and the irbesartan (concentration is up to 50 μ M) of concentration in LBD, do not have direct activation PPAR γ-LBD, therefore do not have replenishing of tangible LXXLL-peptide.
B) SPA-test
Mukherjee R etc.The people has described the SPA-test procedure among J Steroid Biochem Mol Biol (2002) 81:217-225.The test buffer is made up of 20mM Tris pH7.5,25mM KCl, 10mMDTT and 0.2%Triton X-100.30nM GST-PPAR γ-LBD-fusion rotein, 30nMHis-RXR α-LBD, anti-GST-antibody (1: 600, Amersham Pharmacia), 0.25mg a-protein SPA PVT antibody-in conjunction with pearl (Amersham Pharmacia), 30nM 3The Loews lattice row ketone of H-labelling is used the experimental compound diluent, incubated at room temperature 5 hours in 100 μ l cumulative volumes.
Replace radioactive Loews lattice row ketone, add the unlabelled Loews lattice of 10 μ M row ketone and contrast (NSB) as a setting, add used solvent, test material as maximum (Bmax) with replacement as DMSO.
And then with tester in the Hettich of 2000Upm Universal 30Rf-centrifuge centrifugal 5 minutes, and measure after the cultivation at Packard TopCount NXT.
Figure BDA0000053409160000151
Different with direct PPAR γ-agonist (being combined on PPAR γ-LBD), even very big excessive telmisartan, losartan or Ai Boshatan do not have generation to discharge from the concentration dependent of the radioactivity Loews lattice row ketone of binding pocket (tasche) yet.
C) NMR-test
Different with direct PPAR γ-part such as Loews lattice row ketone, having measurement PPAR γ-LBD's in the presence of the experiment material telmisartan 15During N TROSY-spectrum, exchange interaction does not take place in the aminoacid in experiment material and the binding pocket.Having in the presence of the experiment material, showing that the aminoacid of binding pocket when having and not having part to exist is located equally.
Embodiment 2: the PPAR γ of preparation stable conversion-report (Reporter) cell line
A kind of aminoacid 205-505 of the people of coding PPAR γ 2-transcription factor (is equivalent to gene bank-sequence U79012Nucleotide 703-1605) dna fragmentation, through restricted cleavage site BamH I and the Hind III that introduces in addition, and the multiple clone site that enters carrier pFA-CMV (Stratagene), and the checking sequence.The plasmid pFA-CMV/hPPAR γ 2-LBD of gained with the identical frame of Gal4DNA-in conjunction with the territory in.The N-terminal of coding PPAR γ-LBD, this plasmid neomycin resistance of also encoding.
Cell line CHO-K1 (ATCC CCL-61) and plasmid pFA-CMV/hPPAR γ 2-LBD and pFR-Luc (Stratagene) cotransfection.Under the control of five multiple yeast Gal4-binding sites, the plain enzyme gene of pFR-Luc coding fluorescence.According to the maker explanation, carry out transfection with fat transfection amine 2000.
After the transfection, in the presence of 0.5mg/ml G-418, cultured cell in the culture medium with 10% hyclone (Ham ' s F12).Cultivate passage after 6 days, in culture medium, kept again 10 days.Pick the clone body of the neomycin resistance that obtains at microscopically, be distributed in 96-hole-plate and cultivate.Obtain containing the different cell transformed system of plasmid (as clone numbers 10,11,13 etc.), it is continued to be retained in the culture medium.
By PPAR γ-agonist such as Loews lattice row ketone, the inducibility of luciferase gene of research cell line, and with stimulate the luciferase signal reaction that raises by PPAR γ-agonist.
Embodiment 3: the activatory cellulated PPAR γ of telmisartan, losartan and irbesartan
The CHO-K1 cell line that obtains from the clone body 11 of the conversion of embodiment 2 is seeded in In 96-hole-flat underside, density is 3 * 10 4Cell/200 μ l/ holes, and in having the Ham ' s F-12 culture medium of 10% hyclone and 0.5mg/ml G-418 overnight incubation.Change in the culture medium that does not add G-418 after 24 hours.
Make the experiment material reach 100 times of the concentration that requires with suitable solvent such as DMSO, and be diluted to 1: 100 with the substrate that is placed on the Tissue Culture Plate.Contrast as a setting with same concentration with used solvent such as DMSO.
Add material and discard the supernatant after 24 hours
Figure BDA0000053409160000162
, with 150 μ l lavation buffer solution (25mM Tricine, 16.3mM MgSO 4, pH7.8) washed cell is twice.Behind the washing step, adding in each tester has 150 μ l luciferases test buffer (25mM Wheat flavone (Tricine), 0.5mM EDTA, 0.54mM NaTPP, 16.3mM Mg SO 4, 1.2mM ATP, 0.05mM fluorescein, 56.8mM 2 mercapto ethanol, 0.1%Trition X-100,50 μ l lavation buffer solutions pH7.8).On Packard TopCount NXT, measure luminosity after five minutes.Carry out integration to beginning to measure the back plain enzyme unit of initial 10 seconds relative fluorescence (RLU), obtain luciferase-activity.
Figure BDA0000053409160000171
The angiotensin ii receptor antagonist telmisartan can activate the PPAR γ-approach in PPAR γ-report daughter cell system especially doughtily.By other angiotensin ii receptor antagonist such as losartan and irbesartan, only in higher test concentrations and the activation that produces less degree.
Embodiment 4: with the test of 3T3-L1 adipose cell and PC12W cell
In the DMEM with 10% hyclone (FBS) (the eagle culture medium of Dulbecco ' s modification), cultivate 3T3-L1 mouse-forerunner
Figure BDA0000053409160000172
Adipose cell.In the DMEM that 5%FBS and 10% horse serum are arranged, cultivate the PC12W cell.Culture medium all contains 1% penicillin/streptomycin under two kinds of situations.
Cell converges back 2-3 days, and the induced lipolysis cell breaks up by adding a kind of differentiation solution.This differentiation solution contains
1 μ mol/L dexamethasone,
0.5mmol/L 3-isobutyl-1-methylxanthine,
1.67 μ mol/L insulin and
10％FBS。
For relatively, also induce differentiation with the differentiation solution that contains telmisartan in addition.After 48 hours (2 days), this culture medium is used and is contained 10% FBS and the FBS of 1.67 μ mol/L insulins or 10% and the DMEM replacement of 1.67 μ mol/L insulins and telmisartan.It is preceding to carry out ultimate analysis (4 days) at it then, and irritation cell is 48 hours again.
Lipid accumulation in the 3T3-L1 adipose cell
Use the PBS washed cell, and fix 2 minutes with the formalin of 3.7% concentration.After fixing, at room temperature, the oily Red-O with 0.5% made cell painted 1 hour at water with the stock solution in the isopropyl alcohol of dilution in 3: 2.The washing back is this cell of research under optical microscope.
10 μ mol/L telmisartans cause that lipid accumulation increases, and this is by seeing with oily Red-O enhancing is painted.Also promote the differentiation of 3T3-L1 adipose cell by telmisartan.
Stimulate the aP2 in the 3T3-L1 cell to express
Employing is used for the quantification that ABI7000 Sequence Detection (Detetions) system of (Echtzeit) PCR in real time carries out RNA separation, reverse transcription and gene expression (be described in people such as Janke, Diabetes 51:1699-707 is in 2002).The endogenous control that is used for PCR in real time is made of common gene (Haushaltsgene) 18SrRNA and hypoxanthine guanine phosphoribosyltransferase (hprt).
The observed concentration that depends on used telmisartan of inducing.10 μ mol/L telmisartans with about 3.1 ± 0.3 times (p＜0.01) stimulate fat-based in the 3T3-L1 cell because of the expression of marker gene lipoprotein 2 (aP2).By comparison, concentration is that the PPAR γ part Pi Aogelie ketone of 10 μ mol/L stimulates aP2 to express with about 4.5 ± 1 times (p＜0.01).
Transcribe-the reporter test
Whether in order to study the telmisartan induced lipolysis is the result that the PPAR gamma activity stimulates, and transfection experiment is to carry out with PPRE (PPAR replys element)-reporter configuration.Instantaneous (transiente) transfection and the test of used luciferase are described in people such as Kintscher, and Circ Res.91:e35-44 is in 2002.Having in the presence of 1 μ g (for the 3T3-L1 cell) or 50ng (for the PC12W cell) reporter configuration, PPAR γ 2 and RXR alpha expression carrier and the 10ng Renilla luciferase reporter control carrier, with fat transfection amine (Lipofectamine) 2000 (Invitrogen) transfection 3T3-L1 adipose cell (4 days) or PC12W cell.Described reporter configuration is the fusion that 3xAcyl-CoA oxidase PPAR replys element (PPRE) and Tk-luciferase.The PPAR γ 2 and the RXR alpha expression carrier that use are equivalent to people such as Elbrecht, Biochem Biophys Res Com 224:431-437,1996 and people such as Joseph, J Biol Chem 277 (13): 11019-11025, the carrier of describing in 2002.Described luciferase reporter control carrier is plasmid pRL-CMV (Promega).This transfection media is replaced with the DMEM with 10%FBS after 4 hours, and it also contains telmisartan, Pi Aogelie ketone or carrier DMSO.Measure uciferase activity after 24 hours.
Handle with 10 μ mol/L telmisartans The 3T3-L1 adipose cell, cause the inducing of the transcriptional activity of PPAR γ, about 3.4 ± 0.9 times (p＜0.05), as a comparison, 10 inducing of μ mol/L Pi Aogelie ketone are about 5.2 ± 1.1 times.
The PC12W cellBe AT 1-receptor-disappearance.PPAR γ 2 and its heterodimer collocation agent RXR α overexpression in the PC12W cell, and measure have 10 μ mol/L telmisartans or Pi Aogelie ketone to exist or not in the presence of depend on transcribing of PPAR γ.Because the PC12W cell is not expressed PPAR γ, so under the situation that does not have external source PPAR γ 2/RXR α to exist, measure adjusting less than the PPAR gamma activity.But after crossing expression PPAR γ 2/RXR α heterodimer, telmisartan is also induced at AT with 1.9 ± 0.4 times (p＜0.05) 1The PPAR gamma activity of the PC12W cell of-receptor-disappearance.In contrast to this, Pi Aogelie ketone is induced the PPAR gamma activity with 4.2 ± 1.4 times (p＜0.01).This shows that the activation of PPAR gamma activity is to be independent of AT by telmisartan 1The blocking-up of-receptor and taking place.
Data also show, for stimulating the necessary telmisartan concentration of PPAR gamma activity, can obtain in the blood plasma for the treatment of hypertensive patient with telmisartan.This means that can also improve insulin sensitivity in addition with telmisartan treatment hypertension, this plays positive effect to blood sugar level.
Embodiment 5: example of formulations
Tablet 1
By the sodium salt of telmisartan and auxiliary agent and magnesium stearate are directly suppressed, obtain the tablet of following compositions:
Tablet 2
By the sodium salt of telmisartan and auxiliary agent and magnesium stearate are directly suppressed, obtain the tablet of following compositions:
Figure BDA0000053409160000201
Tablet 3
HCTZ thing, the sodium salt of telmisartan, Sorbitol and red iron oxides mix in freely falling body blender (" Free Fall Blender "), sieve by the 0.8mm sieve, after adding magnesium stearate, in the freely falling body blender, be processed into pulverous mixture.
Use suitable tablet machine (as Korsch EKO or Fette P1200) that the compositions of active substance and auxiliary agent is pressed into tablet then.Make the tablet with following compositions, wherein, the amount of every the sodium salt of telmisartan that contains is equivalent to 80mg telmisartan free acid.
Component The mg/ sheet ％
The sodium salt of telmisartan 83,417 13,903
The HCTZ thing 12,500 2,083
Sorbitol 494,483 82,414
Red iron oxides 0,600 0,100
Magnesium stearate 9,000 1,500
Amount to 600,000 100,000
After stirring (75rpm) in 30 minutes, the sodium salt of telmisartan of three batches of tablets is dissolved among the 900ml 0.1M phosphate buffer pH7.5 and reaches 92 ± 1.5%, 96 ± 1.8% or 100 ± 1.0% respectively.After 30 minutes, the dissolving of HCTZ thing reaches 69 ± 6.3%, 72 ± 2.1% or 78 ± 1.8% in 900ml 0.1M HCl (100rpm).

Claims (20)

1. the purposes one of in angiotensin ii receptor antagonist or its salt; it is used to prepare a kind of medicine; this medicine is used for the treatment of and is diagnosed as 2 types true property diabetes or suspection has prediabetic patient, is used for prevent diabetes or is used for the treatment of the metabolic syndrome and the insulin resistance of blood pressure normal patient.
2. according to the purposes of claim 1, it is characterized in that patient's to be treated fasting blood sugar surpasses 125mg glucose/dl blood plasma.
3. according to the purposes of claim 1, it is characterized in that patient's to be treated fasting blood sugar is 110-125mg glucose/dl blood plasma.
4. according to the purposes of claim 1, it is characterized in that, patient to be treated after on an empty stomach taking in the 75g glucose 2 hours, the blood glucose value that records surpasses 200mg glucose/dl blood plasma.
5. according to the purposes of claim 1, it is characterized in that patient to be treated takes in behind the 75g glucose 2 hours on an empty stomach, the blood glucose value that records is 140-200mg glucose/dl blood plasma.
6. according to the purposes of claim 1, it is characterized in that patient's to be treated triglyceride blood values surpasses 150mg/dl.
7. according to the purposes of claim 6, it is characterized in that, patient's to be treated HDL blood values, the women is lower than 40mg/dl blood plasma, and the male is lower than 50mg/dl blood plasma.
8. according to the purposes of claim 6 and 7, it is characterized in that patient's to be treated fasting blood sugar surpasses 110mg glucose/dl blood plasma.
9. according to the purposes of claim 1-8, it is characterized in that patient's to be treated systolic blood pressure value surpasses 140mm Hg and the diastolic blood pressure value surpasses 90mm Hg.
10. according to claim 1,2 and 4 purposes, it is characterized in that patient's to be treated systolic blood pressure value surpasses 130mm Hg and the diastolic blood pressure value surpasses 80mm Hg.
11. the purposes according to claim 1-10 is characterized in that, patient's to be treated WHR, the women surpass 0.8 or the male surpass 1.
12. purposes according to claim 1, it is characterized in that, this angiotensin ii receptor antagonist has following character: after the PPAR γ-report daughter cell that adds stable conversion is tied in the culture medium, the expression of the luciferase gene of its activation stable transfection, and be not attached on the PPAR γ ligand binding domain external.
13. purposes according to claim 12, it is characterized in that, this angiotensin ii receptor antagonist does not have demonstration to be attached on the ligand binding domain of people PPAR γ receptor external, if and after joining it in the culture medium of cell line of stable conversion, this angiotensin ii receptor antagonist causes the plain enzymatic activity of induced fluorescence, a kind of fusion rotein of forming in conjunction with the territory by the ligand binding domain and the yeast GAL4 DNA of people PPAR γ transcription factor of this expression of cell lines, and contain a kind of luciferase gene under five multiple yeast Gal4-binding site control.
14. the purposes according to claim 1 is characterized in that, this angiotensin ii receptor antagonist is the active substance telmisartan.
15. the purposes according to claim 1 is characterized in that, the form of administration of this medicine contains the 20-200mg telmisartan.
16. the purposes according to claim 1 is characterized in that, this angiotensin ii receptor antagonist and diuretic combination.
17. the purposes according to claim 16 is characterized in that, the form of administration of this medicine contains 10-50mgHCTZ or chlortalidone.
18. be used for the treatment of and be diagnosed as 2 types true property diabetes or suspection has prediabetic people, is used for prevent diabetes or the metabolic syndrome of treatment blood pressure normal patient and the method for insulin resistance; it is characterized in that, with a kind of drug administration that contains angiotensin ii receptor antagonist.
19. the method according to claim 18 is characterized in that, this angiotensin ii receptor antagonist is the active substance telmisartan.
20. contain the pharmaceutical composition of telmisartan and following material:
A) amlodipine or nifedipine,
B) eplerenone or spironolactone,
C) simvastatin or atorvastatin,
D) Loews lattice row ketone or Pi Aogelie ketone or repaglinide or metformin,
E) dipyridamole or clopidogrel make up aspirin in case of necessity,
F) aldosterone antagonists,
G) HMG-Co A reductase inhibitor,
H) DPP4 inhibitor,
I) sulfonylureas or
J) platelet-agglutination inhibitor.
CN2011100821828A 2003-07-31 2004-07-24 Use of angiotensin II receptor antagonists, especially telmisartan, in order to increase insulin sensitivity Pending CN102139110A (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
DE10335027A DE10335027A1 (en) 2003-07-31 2003-07-31 Use of telmisartan and simvastatin for treatment or prophylaxis of cardiovascular, cardiopulmonary and renal diseases e.g. hypertension combined with hyperlipidemia or atherosclerosis
DE10335027.6 2003-07-31
DE10346260.0 2003-10-06
DE10346260A DE10346260A1 (en) 2003-07-31 2003-10-06 Use of an angiotensin II receptor antagonist for treating type 2 diabetes or prediabetes, for preventing diabetes or for treating metabolic syndrome and insulin resistance in patients with normal blood pressure
DE10356815.8 2003-12-05
DE10356815A DE10356815A1 (en) 2003-07-31 2003-12-05 Use of an angiotensin II receptor antagonist for treating type 2 diabetes or prediabetes, for preventing diabetes or for treating metabolic syndrome and insulin resistance in patients with normal blood pressure

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN2004800220966A Division CN1829511B (en) 2003-07-31 2004-07-24 Use of telmisartan and amlodipine or Nifedipine in preparing medicine for increasing insulin sensitivity

Publications (1)

Publication Number Publication Date
CN102139110A true CN102139110A (en) 2011-08-03

Family

ID=34119379

Family Applications (3)

Application Number Title Priority Date Filing Date
CN2011100821828A Pending CN102139110A (en) 2003-07-31 2004-07-24 Use of angiotensin II receptor antagonists, especially telmisartan, in order to increase insulin sensitivity
CN2004800220966A Withdrawn - After Issue CN1829511B (en) 2003-07-31 2004-07-24 Use of telmisartan and amlodipine or Nifedipine in preparing medicine for increasing insulin sensitivity
CN2010102582634A Pending CN101926997A (en) 2003-07-31 2004-07-24 Angiotensin, particularly telmisartan are used to improve the purposes of insulin sensitivity

Family Applications After (2)

Application Number Title Priority Date Filing Date
CN2004800220966A Withdrawn - After Issue CN1829511B (en) 2003-07-31 2004-07-24 Use of telmisartan and amlodipine or Nifedipine in preparing medicine for increasing insulin sensitivity
CN2010102582634A Pending CN101926997A (en) 2003-07-31 2004-07-24 Angiotensin, particularly telmisartan are used to improve the purposes of insulin sensitivity

Country Status (29)

Country Link
US (1) US20050070594A1 (en)
EP (3) EP2119441B1 (en)
JP (1) JP4833840B2 (en)
KR (1) KR20060054404A (en)
CN (3) CN102139110A (en)
AT (1) ATE443519T1 (en)
AU (1) AU2004260606B2 (en)
BR (1) BRPI0413165A (en)
CA (1) CA2534006C (en)
CY (1) CY1109560T1 (en)
DE (4) DE10335027A1 (en)
DK (2) DK1651213T4 (en)
EA (2) EA017640B1 (en)
EC (1) ECSP066303A (en)
ES (2) ES2543722T3 (en)
HK (1) HK1093305A1 (en)
HU (1) HUE027274T2 (en)
IL (1) IL172693A (en)
ME (1) MEP51108A (en)
MX (1) MXPA06001322A (en)
NO (1) NO335444B1 (en)
NZ (1) NZ544877A (en)
PL (2) PL1651213T5 (en)
PT (1) PT1651213E (en)
RS (1) RS50793B (en)
SI (1) SI1651213T2 (en)
UA (1) UA83854C2 (en)
WO (1) WO2005011680A1 (en)
ZA (1) ZA200509835B (en)

Families Citing this family (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE353900T1 (en) * 2001-02-24 2007-03-15 Boehringer Ingelheim Pharma XANTHINE DERIVATIVES, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US7501426B2 (en) 2004-02-18 2009-03-10 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
US20060078615A1 (en) * 2004-10-12 2006-04-13 Boehringer Ingelheim International Gmbh Bilayer tablet of telmisartan and simvastatin
DE102004054054A1 (en) 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines
JP5134963B2 (en) * 2004-11-05 2013-01-30 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Bilayer tablet containing telmisartan and amlodipine
CN1298389C (en) * 2005-01-18 2007-02-07 广东省人民医院 Compound preparation of calcium antagonist and timishatan for reducing blood pressure and its use
WO2006136916A2 (en) * 2005-06-20 2006-12-28 Glenmark Pharmaceuticals Limited Substantially pure micronized particles of telmisartan and pharmaceutical compositions containing same
DE102005035891A1 (en) 2005-07-30 2007-02-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8- (3-amino-piperidin-1-yl) -xanthines, their preparation and their use as pharmaceuticals
EP1942921A4 (en) * 2005-10-25 2011-03-09 Merck Sharp & Dohme Combination of a dipeptidyl peptidase-4 inhibitor and an anti-hypertensive agent for the treatment of diabetes and hypertension
EP1852108A1 (en) * 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG DPP IV inhibitor formulations
CN102838599A (en) 2006-05-04 2012-12-26 贝林格尔.英格海姆国际有限公司 Polymorphs
PE20080251A1 (en) 2006-05-04 2008-04-25 Boehringer Ingelheim Int USES OF DPP IV INHIBITORS
EP2051696A2 (en) * 2006-08-18 2009-04-29 Morton Grove Pharmaceuticals, Inc. Stable liquid levetiracetam compositions and methods
EP1908469A1 (en) 2006-10-06 2008-04-09 Boehringer Ingelheim Vetmedica Gmbh Angiotensin II receptor antagonist for the treatment of systemic diseases in cats
CN101260103A (en) * 2007-03-09 2008-09-10 上海艾力斯医药科技有限公司 Compound with portion PPARgamma excitant activity and application thereof
EP2134326B1 (en) * 2007-04-17 2011-11-16 Ratiopharm GmbH Pharmaceutical compositions comprising irbesartan
PE20140960A1 (en) 2008-04-03 2014-08-15 Boehringer Ingelheim Int FORMULATIONS INVOLVING A DPP4 INHIBITOR
BRPI0916997A2 (en) 2008-08-06 2020-12-15 Boehringer Ingelheim International Gmbh DPP-4 INHIBITOR AND ITS USE
UY32030A (en) 2008-08-06 2010-03-26 Boehringer Ingelheim Int "TREATMENT FOR DIABETES IN INAPPROPRIATE PATIENTS FOR THERAPY WITH METFORMIN"
AU2009290911A1 (en) 2008-09-10 2010-03-18 Boehringer Ingelheim International Gmbh Combination therapy for the treatment of diabetes and related conditions
US20200155558A1 (en) 2018-11-20 2020-05-21 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
AU2009331471B2 (en) 2008-12-23 2015-09-03 Boehringer Ingelheim International Gmbh Salt forms of organic compound
AR074990A1 (en) 2009-01-07 2011-03-02 Boehringer Ingelheim Int TREATMENT OF DIABETES IN PATIENTS WITH AN INAPPROPRIATE GLUCEMIC CONTROL THROUGH METFORMIN THERAPY
CN101869567A (en) * 2009-04-24 2010-10-27 北京奥萨医药研究中心有限公司 Medicament composition containing biguanide antidiabetic medicament and sartan antihypertensive medicament and applications thereof
ES2598490T3 (en) 2009-05-20 2017-01-27 Boehringer Ingelheim Vetmedica Gmbh Telmisartan drinkable pharmaceutical solution
KR101069166B1 (en) * 2009-06-02 2011-09-30 한국화학연구원 Pharmaceutical composition for the prevention or treatment of osteoporosis or obesity comprising an imidazo phenyltetrazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient
KR102668834B1 (en) 2009-11-27 2024-05-24 베링거 인겔하임 인터내셔날 게엠베하 Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin
ES2935300T3 (en) 2010-05-05 2023-03-03 Boehringer Ingelheim Int combitherapy
KR20230051307A (en) 2010-06-24 2023-04-17 베링거 인겔하임 인터내셔날 게엠베하 Diabetes therapy
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
KR102117282B1 (en) * 2010-11-15 2020-06-01 베링거 인겔하임 인터내셔날 게엠베하 Vasoprotective and cardioprotective antidiabetic therapy
EA030121B1 (en) 2011-07-15 2018-06-29 Бёрингер Ингельхайм Интернациональ Гмбх Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
WO2013171167A1 (en) 2012-05-14 2013-11-21 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
ES2950384T3 (en) 2014-02-28 2023-10-09 Boehringer Ingelheim Int Medical use of a DPP-4 inhibitor
EP4233840A3 (en) 2016-06-10 2023-10-18 Boehringer Ingelheim International GmbH Combinations of linagliptin and metformin
RU2699508C1 (en) * 2018-07-25 2019-09-05 Федеральное государственное бюджетное образовательное учреждение высшего образования "Северо-Осетинская государственная медицинская академия" Министерства здравоохранения Российской Федерации Method of treating patients with metabolic syndrome
CN114073697B (en) * 2021-01-19 2023-01-24 复旦大学附属肿瘤医院 Application of BCAT2 inhibitor in preparation of medicines for preventing and/or treating BCAT 2-mediated related metabolic diseases
CN114786683B (en) 2021-04-09 2024-01-12 北京大学 siRNA, pharmaceutical composition and method for treating diabetes by using siRNA and pharmaceutical composition

Family Cites Families (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4265847A (en) * 1978-03-30 1981-05-05 Kirby Pharmaceuticals Ltd Tabletting process
JPS5671074A (en) 1979-11-12 1981-06-13 Takeda Chem Ind Ltd 1,2-disubstituted-4-halogenoimidazole-5-acetic acid derivative
DK161312C (en) * 1982-03-11 1991-12-09 Pfizer CHANGES FOR THE PREPARATION FOR THE PREPARATION OF 2-Amino-CO-Methyl-4-Methyl-4-Methyl-4-Methyl-4-Methyl-4-Methyl-4-Methyl-2-D-Hydroxy
CA1334092C (en) 1986-07-11 1995-01-24 David John Carini Angiotensin ii receptor blocking imidazoles
US4880804A (en) 1988-01-07 1989-11-14 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking benzimidazoles
CA1338238C (en) 1988-01-07 1996-04-09 David John Carini Angiotensin ii receptor blocking imidazoles and combinations thereof with diuretics and nsaids
US5015651A (en) 1988-01-07 1991-05-14 E. I. Du Pont De Nemours And Company Treatment of hypertension with 1,2,4-angiotensin II antagonists
IE70593B1 (en) 1989-09-29 1996-12-11 Eisai Co Ltd Biphenylmethane derivative the use of it and pharmacological compositions containing same
DE122007000050I1 (en) 1990-02-19 2007-11-08 Novartis Ag acyl compounds
PT97078B (en) 1990-03-20 1997-07-31 Sanofi Sa PROCESS FOR THE PREPARATION OF N-SUBSTITUTED HETEROCYCLIC DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US5196444A (en) 1990-04-27 1993-03-23 Takeda Chemical Industries, Ltd. 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof
IL99246A0 (en) 1990-09-10 1992-07-15 Abbott Lab Angiotensin ii receptor antagonists and pharmaceutical compositions containing them
SI9210098B (en) 1991-02-06 2000-06-30 Dr. Karl Thomae Benzimidazoles, drugs with this compounds, and process for their preparation
US5196537A (en) 1991-03-21 1993-03-23 G. D. Searle & Co. 5-apylheteroarylalkyl-1,3,5-trisubstituted-1,2,4-triazole compounds for treatment of circulatory disorders
GB9110636D0 (en) 1991-05-16 1991-07-03 Glaxo Group Ltd Chemical compounds
US6162802A (en) * 1992-03-10 2000-12-19 Papa; Joseph Synergistic combination therapy using benazepril and amlodipine for the treatment of cardiovascular disorders and compositions therefor
JPH07505646A (en) 1992-04-13 1995-06-22 ゼネカ・リミテッド Angiotensin II antagonists for disorders involving impaired nerve conduction velocity, especially diabetic neuropathy
US5824696A (en) 1993-09-01 1998-10-20 Smithkline Beecham Corporation Medicaments
JP3883205B2 (en) 1994-03-29 2007-02-21 メルク エンド カンパニー インコーポレーテッド Treatment of Atherosclerosis with Angiotensin II Receptor Blocking Imidazole
US5496831A (en) * 1994-05-13 1996-03-05 The General Hospital Corporation Inhibition of insulin-induced adiposis
EP0831911B1 (en) * 1995-06-07 2002-04-17 G.D. Searle & Co. Spironolactone and angiotensin ii antagonist combination therapy for treatment of congestive heart failure
US6087386A (en) * 1996-06-24 2000-07-11 Merck & Co., Inc. Composition of enalapril and losartan
US20030077229A1 (en) * 1997-10-01 2003-04-24 Dugger Harry A. Buccal, polar and non-polar spray or capsule containing cardiovascular or renal drugs
JP4588877B2 (en) * 1998-06-17 2010-12-01 ブリストル−マイヤーズ スクイブ カンパニー Prevention of cerebral infarction by combined administration of ADP-receptor antiplatelet substance and antihypertensive drug
CN1234357C (en) * 1998-07-10 2006-01-04 诺瓦提斯公司 Antihypersensitive combination of valsartan and calcium channel blocker
AU1042199A (en) * 1998-11-06 2000-05-29 Boehringer Ingelheim International Gmbh Antihypertensive medicaments containing lacidipine and telmisartan
UA74141C2 (en) 1998-12-09 2005-11-15 Дж.Д. Сірл Енд Ко. Oral pharmaceutical compositions comprising micronized eplerenone (variants), method for its production and method for treating aldosterone-mediated states (variants)
WO2000066161A1 (en) * 1999-04-28 2000-11-09 Takeda Chemical Industries, Ltd. Preventives / remedies / progression inhibitors for simplex retinopathy or preproliferating retinopathy
EP1093814A1 (en) * 1999-10-22 2001-04-25 Boehringer Ingelheim Pharma KG Use of dipyridamole or mopidamol in the manufacture of a medicament for the treatment and prevention of fibrin-dependent microcirculation disorders
EP1326604A2 (en) * 2000-04-12 2003-07-16 Novartis AG Combination of at least two compounds selected from an at1-receptorantagonist or an ace inhibitor or a hmg-co-a reductase inhibitor groups
US6784207B2 (en) * 2000-08-04 2004-08-31 Roche Vitamins Inc. Phytanic acid derivative compositions
WO2002043807A2 (en) * 2000-12-01 2002-06-06 Novartis Ag Combinations of an angiotensin receptor antagonist and an anti-hypertensive drug or a statin, for the treatment of sexual dysfunction
US20030078190A1 (en) * 2001-05-25 2003-04-24 Weinberg Marc S. Methods for tissue protection using highly effective inhibition of the renin-angiotensin system
JP2003113120A (en) * 2001-08-03 2003-04-18 Takeda Chem Ind Ltd Sustained release medicine
US6576256B2 (en) * 2001-08-28 2003-06-10 The Brigham And Women's Hospital, Inc. Treatment of patients at elevated cardiovascular risk with a combination of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin
US20030114469A1 (en) * 2001-09-27 2003-06-19 Cohen David Saul Combinations
AUPS236902A0 (en) * 2002-05-16 2002-06-13 Northern Sydney Area Health Service Composition and method for treating hypertension
US7232828B2 (en) * 2002-08-10 2007-06-19 Bethesda Pharmaceuticals, Inc. PPAR Ligands that do not cause fluid retention, edema or congestive heart failure
US8980870B2 (en) * 2002-09-24 2015-03-17 Boehringer Ingelheim International Gmbh Solid telmisartan pharmaceutical formulations
AU2004204353A1 (en) * 2003-01-16 2004-07-29 Boehringer Ingelheim International Gmbh Pharmaceutical combination for the prophylaxis or treatment of cardiovascular, cardiopulmonary, pulmonary or renal diseases
DE10301371A1 (en) * 2003-01-16 2004-08-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg Treatment or prophylaxis of cardiovascular, cardiopulmonary or renal diseases, e.g. hypertension combined with hyperlipidemia or atherosclerosis, using combination of telmisartan and atorvastatin
DE10306179A1 (en) * 2003-02-13 2004-08-26 Boehringer Ingelheim Pharma Gmbh & Co. Kg Composition useful for preventing stroke comprises dipyridamole or its salt, acetyl salicylic acid and an angiotensin II antagonist
US9029363B2 (en) * 2003-04-30 2015-05-12 Boehringer Ingelheim International Gmbh Telmisartan sodium salt pharmaceutical formulation

Also Published As

Publication number Publication date
DK1651213T3 (en) 2010-02-01
BRPI0413165A (en) 2006-10-03
NZ544877A (en) 2009-04-30
EP2119441A1 (en) 2009-11-18
EP2263670B1 (en) 2015-09-09
IL172693A0 (en) 2006-04-10
DE10335027A1 (en) 2005-02-17
UA83854C2 (en) 2008-08-26
HUE027274T2 (en) 2016-10-28
SI1651213T2 (en) 2013-04-30
DE10346260A1 (en) 2005-04-28
EP2119441B1 (en) 2015-05-20
EP1651213B2 (en) 2013-01-23
IL172693A (en) 2012-10-31
DE502004010117D1 (en) 2009-11-05
CN101926997A (en) 2010-12-29
PL1651213T5 (en) 2013-04-30
EA200600161A1 (en) 2006-08-25
EP2263670A1 (en) 2010-12-22
CN1829511B (en) 2011-08-17
RS50793B (en) 2010-08-31
AU2004260606A1 (en) 2005-02-10
DK2119441T3 (en) 2015-08-10
EP1651213A1 (en) 2006-05-03
PL1651213T3 (en) 2010-03-31
MEP51108A (en) 2011-02-10
ATE443519T1 (en) 2009-10-15
RS20060066A (en) 2008-08-07
NO20060938L (en) 2006-02-27
EA012600B1 (en) 2009-10-30
WO2005011680A8 (en) 2009-07-16
EP1651213B1 (en) 2009-09-23
AU2004260606B2 (en) 2010-12-09
ECSP066303A (en) 2006-10-25
HK1093305A1 (en) 2007-03-02
CA2534006C (en) 2010-07-13
EA017640B1 (en) 2013-02-28
US20050070594A1 (en) 2005-03-31
WO2005011680A1 (en) 2005-02-10
DK1651213T4 (en) 2013-04-15
KR20060054404A (en) 2006-05-22
CN1829511A (en) 2006-09-06
JP4833840B2 (en) 2011-12-07
DE10356815A1 (en) 2005-07-07
CY1109560T1 (en) 2014-08-13
SI1651213T1 (en) 2010-01-29
MXPA06001322A (en) 2006-05-04
CA2534006A1 (en) 2005-02-10
ES2543722T3 (en) 2015-08-21
ES2334136T3 (en) 2010-03-05
PL2119441T3 (en) 2015-10-30
PT1651213E (en) 2009-10-15
EA200900929A1 (en) 2010-04-30
NO335444B1 (en) 2014-12-15
ES2334136T5 (en) 2013-05-21
ZA200509835B (en) 2006-11-29
JP2007500677A (en) 2007-01-18

Similar Documents

Publication Publication Date Title
CN1829511B (en) Use of telmisartan and amlodipine or Nifedipine in preparing medicine for increasing insulin sensitivity
Choi et al. Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation
CN100548293C (en) Can not cause the Novel PPAR ligands of liquid pool stream, edema or congestive heart failure
US8268837B2 (en) Use of c-Src inhibitors alone or in combination with STI571 for the treatment of leukaemia
CN107427698A (en) The combination treatment of pulmonary hypertension
CN104159589A (en) Treatment of liver conditions
CA2513281C (en) Pharmaceutical combination for the prevention or treatment of cardiovascular, cardiopulmonary, pulmonary or renal diseases
JP2007269630A (en) Insulin secretion promoter
Stover Dinaciclib Inhibits Glioblastoma Multiforme Cell Growth and Selects for a Brain Tumour Initiating Cell Population
UA81290C2 (en) Use of telmisartan and simvastatin, pharmaceutical composition and treatment method
WO2005070432A1 (en) Use of pdgf-r tk inhibitors for the treatment of myocarditis and its complications

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C12 Rejection of a patent application after its publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20110803